Summary The ACCORD study tested the hypothesis that intensive glucose management would reduce cardiovascular disease in type 2 diabetes patients with known cardiovascular risk factors. Although intensive therapy targeting near normal hemoglobin A1c levels (6%) did not reduce major cardiovascular events, the study documented increased mortality as a previously unrecognized harm of intensive glucose lowering therapy in high-risk patients with type 2 diabetes. Intensive glycemic control and combination treatment of dyslipidemia reduced the rate of progression of diabetic retinopathy and delayed the onset of albuminuria. However, these microvascular benefits of intensive management did not clearly outweigh the concomitant increased risk for severe hypoglycemia or total or cardiovascular disease-related mortality. Symptomatic severe hypoglycemia was associated with increased risk of death in both the intensive and standard therapy groups but did not explain the greater mortality observed in the intensive therapy group. This proposal will evaluate data from the ACCORD study to determine if biological variation in hemoglobin A1c is associated with clinical outcomes of intensive glycemic control in type 2 diabetes. Some individuals, families and ethnic groups have consistently higher than average A1c levels independent of the effects of blood glucose concentration. The hemoglobin glycation index (HGI) measures hemoglobin A1c controlled for blood glucose and is a biomarker of risk for microvascular complications above and beyond the effects of blood glucose concentration. Potential associations between HGI and diabetes complications other than microvascular have not been studied. High HGI is characterized by persistently higher than average A1c levels independent of blood glucose concentration. Significantly, the ACCORD study reported that higher A1c levels were associated with greater risk of mortality in the intensively treated group. We hypothesize that HGI reflects hereditary influences on metabolism that contribute to hemoglobin glycation and risk for macrovascular and microvascular complications. Since high HGI patients have lower blood glucose levels compared to low HGI patients with a similar A1c, we speculate that intensive management of high HGI patients to a low A1c target could inadvertently produce lower than expected blood glucose levels. Our specific aims are to determine if high HGI is associated with greater risk for 1) mortality and cardiovascular events, 2) progression of microvascular disease, and 3) hypoglycemia. The results could help explain excess mortality in the ACCORD intensive treatment group. The results may also validate the clinical use of HGI for assessment of complications risk in type 2 diabetes. Evidence that high HGI patients are more susceptible to hypoglycemia would recommend the clinical use of HGI for identifying high-risk individuals which would allow physicians to personalize treatment to an individualized low A1c target that would minimize both acute (hypoglycemia) and chronic (macrovascular and microvascular) diabetes complications. 1